1. Field of the Invention
The present invention relates to new nucleoside derivatives possessing anti-tumor activity and to processes for the preparation of such derivatives. More particularly, the present invention relates to new 5-fluorouridine, 2'-deoxy-5-fluorouridine and 1-.beta.-D-arabinofuranosyl-5-fluorouracil derivatives carrying a nitrogen-containing acyl group in the 5'-position thereof and possessing strong anti-tumor activity in combination with low toxicity as well as processes for the preparation of such derivatives wherein the nitrogen-containing acyl group is introduced directly in one step or indirectly in two steps into the 5'-position of 5-fluorouridine, 2'-deoxy-5-fluorouridine or 1-.beta.-D-arabinofuranosyl-5-fluorouracil.
2. Description of the Prior Art
5-Fluorouridine, 2'-deoxy-5-fluorouridine and 1-.beta.-D-arabinofuranosyl-5-fluorouracil, which constitute the main skeletal structure of the new nucleoside derivatives of the present invention, are all known as nucleosides. These compounds are already known to have anti-tumor activity, anti-bacterial activity and the like pharmacological properties. In fact, studies on syntheses and pharmacological properties of these known compounds are reported and disclosed, for example, in British Pat. No. 1,080,491 and U.S. Pat. No. 2,885,396, Proceedings of the Society for Experimental Biology and Medicine 97, 470 (1958) and Physicians' Desk Reference 34, 1455 (1980). However, these compounds are ill-balanced between pharmacological properties and toxicity. If the anti-tumor activity alone is taken up among these pharmacological properties, these known compounds exhibit undesirably high toxicity at a level where the anti-tumor activity becomes effective. For these reasons, therefore, 2'-deoxy-5-fluorouridine alone is practically used as an anti-tumor agent only by way of a troublesome intrarterial injection because this compound is hardly absorbed merely by way of oral administration. Accordingly, a number of researches have been made on syntheses and anti-tumor activity of functional derivatives of these nucleosides for overcoming such disadvantages of the known nucleosides and discovering new pharmacologically effective derivatives thereof. A part of the researches is directed to synthesis and anti-tumor activity of esters of the nucleosides with fatty acids, and is disclosed, for example, in British Pat. No. 1,080,491, Biochemical Pharmacology 14, 1605 (1965), ibid. 15, 627 (1966), and Japanese Laid-open Patent Applns. Nos. 82079/70, 83378/70, 64280/75, 93983/75 and 133286/76. In all of these esters, however, the anti-tumor activity is not improved to a practically permissible extent. Another part of the researches is directed to synthesis and anti-tumor activity of esters of the nucleosides with phosphoric acid and its derivatives, and is disclosed, for example, in Proceedings of the Society for Experimental Biology and Medicine 104, 127 (1960), Cancer Research 22, 815 (1962), and Japanese Laid-open Patent Appln. No. 31677/78. The majority of these phosphoric esters are active forms of the nucleosides and are naturally supposed to be stronger in anti-tumor activity than the starting nucleosides. Actually, however, the anti-tumor activity of these esters does not reach a satisfactory level.
From the chemotherapeutic point of view, it is of importance that the synthesized derivatives of these nucleosides have to possess a high anti-tumor activity with a minimum level of toxicity. However, all the derivatives of the nucleosides synthesized hitherto are scarcely improved in anti-tumor activity so that if they are used in a dose sufficient enough to achieve the desired level of anti-tumor activity, their toxicity is concurrently increased to a practically impermissible extent.
Thus, there is still a great demand in this art for developing new derivatives of the nucleosides possessing a strong anti-tumor activity with a weak toxicity by chemically modifying the nucleosides in a simple manner.